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Richter’s transformation (RT) is defined as the evolution of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. This complication is rare and aggressive, with poor prognosis and dismal survival. Clonal relationship with the underlying CLL/SLL, observed in ∼80% of cases, represents one of the main factors affecting prognosis. Treatment has been historically based on chemoimmunotherapy, but frequent mutations in genes involved in cell survival and proliferation—such as TP53, NOTCH1, MYC, CDKN2A—confer resistance to standard treatments. During the last years, advances in the knowledge of the biological mechanisms underlying RT allowed to identify genetic and molecular lesions that can potentially be targeted by novel selective agents. Pathway and checkpoint inhibitors, bispecific antibodies and CAR T-cell therapy are currently under investigation and represent promising treatment options. This review summarizes current biological evidence and available data on novel therapeutic agents.

The importance of coexisting conditions in chronic lymphocytic leukemia (CLL) outcome has been increasingly recognized over the past years. The role of comorbidities to predict patients’ vulnerability toward immunochemotherapy has been well establish, especially since some of the tools commonly used to evaluate patients’ fitness were employed to determine treatment eligibility in randomized trials. Nevertheless, is it still unclear how much fitness weights on treatment outcome with targeted agents and which assessment should be preferred. There are key differences in the toxicity profile between novel agents that are getting much more evident in retrospective, real-life experiences, rather than clinical trials. Therefore, an individual patient's comorbid medical conditions may be a deciding factor in therapy selection. Here, we analyze main evidence in literature on the predicting value of comorbidity assessment on outcome and management of CLL patients receiving novel agents.

Waldenström Macroglobulinemia (WM) is a rare indolent lymphoma with heterogeneous clinical presentation. As there are no randomised trials suggesting the best treatment option in treatment-naive patients, guidelines suggest either rituximab-combining regimens or BTK-inhibitors (BTKi) as feasible alternatives. Several factors play in the decision-making process: patients’ age and fitness, disease characteristics and genotype. Chemoimmunotherapy (CIT) represents a fixed-duration, less expensive and effective option, able to achieve prolonged time-to-next treatment even in patients with unfavourable genotypes. Immunosuppression and treatment-related second cancers may represent serious concerns. Proteasome-inhibitor-based regimens are effective with rapid disease control, although bortezomib-related neuropathy discourages the choice of these agents and treatment schedules may not be easily manageable in the elderly. BTKi have demonstrated high rates of response and prolonged survival together with the convenience of an oral administration and limited cytopenias. However, outcomes are impacted by genotype and some concerns remain, in particular the continuous drug exposure that may result in extra-haematological complications and drug resistance. Although next-generation BTKi have improved treatment tolerance, the question whether BTKi should be offered as frontline therapy to every patient is still debated. Giving fixed-duration schedule, prolonged time-to-next treatment and outcomes independent of genotype, CIT is still our preferred choice in WM. However, BTKi remain a valuable option in frail patients unsuitable for CIT.

Ibrutinib revolutionized the CLL treatment approach and prognosis demonstrating its efficacy and safety even at extended follow-up. During the last few years, several next-generation inhibitors have been developed to overcome the occurrence of toxicity or resistance in patients on continuous treatment. In a head-to-head comparison of two phase III trials, both acalabrutinib and zanubrutinib demonstrated a lower incidence of adverse events in respect to ibrutinib. Nevertheless, resistance mutations remain a concern with continuous therapy and were demonstrated with both first- and next-generation covalent inhibitors. Reversible inhibitors showed efficacy independently of previous treatment and the presence of BTK mutations. Other strategies are currently under development in CLL, especially for high-risk patients, and include BTK inhibitor combinations with BCl2 inhibitors with or without anti-CD20 monoclonal antibodies. Finally, new mechanisms for BTK inhibition are under investigations in patients progressing with both covalent and non-covalent BTK and BCl2 inhibitors. Here we summarize and discuss results from main experiences on irreversible and reversable BTK inhibitors in CLL.

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS . 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients’ vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

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Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton's tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (<10−4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax ± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax ± ibrutinib. Patients with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24–88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value (p = 0.044), frequency of circulating hairy cells (p = 0.039), recovery of absolute neutrophil count (p = 0.006), and normalization of spleen (p ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04–28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p < 0.0001). Non-hematological grade 3 or higher early toxicity was reported in 103 (20.1%) patients. Median OS was not reached: 95.3%, 92.4%, and 81.8% of patients were estimated to be alive at 5, 10, and 15 years, respectively. Forty-nine patients died (9.5%), following an infection in 14 cases (2.7%), natural causes in 14 (2.7%), cardiovascular events in 13 (2.5%), a second neoplasm in 6 (1.2%), and progression of HCL in 2 cases (0.4%). Following treatment of HCL with 2CDA, 80% of patients are estimated to be alive 15 years after diagnosis.

Introduction: Chemoimmunotherapy has improved outcomes in chronic lymphocytic leukemia, yet it is not curative, with very high relapse rates, and is associated with a significant risk of toxicities. Moreover, patients with higher-risk genetic abnormalities continue to experience poorer outcomes and lower survival. Recently, novel targeted therapies have been developed to increase efficacy and reduce toxicity. Areas covered: Ibrutinib is an oral irreversible inhibitor of Bruton’s tyrosine kinase, a mediator of B-cell receptor signaling, which plays a vital role in various B-cell neoplasms. The drug has been approved for the treatment of several hematological malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma, where large trials have shown outcomes never seen before even in high-risk patients. The safety profile appeared furthermore favorable, even in elderly and unfit patients. Expert opinion: Therapy with ibrutinib rarely provides MRD-negative complete remission; an indefinite maintenance is therefore needed, with the risk of developing adverse events (AE) or resistance resulting in treatment interruption or discontinuation. Novel, extremely promising, combination strategies, based on the association of ibrutinib with chemoimmunotherapy, anti-CD20 monoclonal antibody or other targeted agents, are currently being investigated, with the goal of achieving greater depth of remission, especially MRD-negativity, and removing the need for indefinite treatment.

Waldenstrom Macroglobulinemia is a rare lymphoproliferative disorder with distinctive clinical features. Diagnostic and prognostic characterisation in WM significantly changed with the discovery of two molecular markers: MYD88 and CXCR4. Mutational status of these latter influences both clinical presentation and prognosis and demonstrated therapeutic implications. Treatment choice in Waldenstrom disease is strictly guided by patients age and characteristics, specific goals of therapy, the necessity for rapid disease control, the risk of treatment-related neuropathy, disease features, the risk of immunosuppression or secondary malignancies and potential for future autologous stem cell transplantation. The therapeutic landscape has expanded during the last years and the approval of ibrutinib, the first drug approved for Waldenstrom Macroglobulinemia, represents a significant step forward for a better management of the disease.

Ibrutinib represents a revolution in chronic lymphocytic leukemia treatment scenario providing results never seen before and offering an effective therapy even in high-risk patients with really poor outcome after chemoimmunotherapy. Thanks to longer updates, on one hand, ibrutinib has confirmed its efficacy continuing to show clinical benefits over time; on the other hand, resistance mechanisms are slowly emerging. Moreover, clinicians should be aware of ibrutinib-related side effects, paying attention to screen patients that could benefit more from the drug and try to prevent adverse events. While ibrutinib approval indication is expanding, high treatment costs will shortly require a selection of those who can really draw advantage from Bruton's tyrosine kinase inhibition and those who could continue to be treated with chemoimmunotherapy.

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous stem cell transplantation. Overall, 19% of patients received ibrutinib during the course of the disease. According to IPSSWM, 63% were classified as low risk, 27% as intermediate risk and 10% as high risk. Five-year OS was shorter in high-risk as compared with low or intermediate risk patients (92.9% vs 100% P =.002). According to revised IPSSWM, 92% were classified as very low or low risk and 8% as intermediate risk, with a shorter 5-year OS in the latter group (87.5% vs 100%, P =.028). The OS of young WM patients was not significantly reduced as compared with age-matched, sex-matched and calendar year-matched general population. Early diagnosis, absence of high-risk features in symptomatic patients and high efficacy of modern treatments are the main determinants of the excellent outcome of young WM patients.

Twenty-three cases of hereditary demyelinating neuropathies are reported, 13 with different types of hereditary motor and sensory neuropathy (HMSN) and 9 with globoid cell or meta-chromatic leucodystrophies. Ultrastructural and morpho-metric studies showed some critical pathological features emphasizing: 1) the variability of the recessive forms of HMSN; 2) the morphological distinction between HMSN type I and type III; and 3) differences between these types of HMSN and other ''onion bulb'' neuropathies such as those found in leucodystrophies, which account for distinct underlying mechanisms.

WILLIAMS SYNDROME: REPORT OF A CASE REFLECTING PULMONARY VALVE STENOSIS A patient affected by Williams Syndrome is described. He presented “elfin face”, neurological disorders and cardiac malformations. The presence of a severe pulmonary valve stenosis is pointed out. This type of malformation is rare in Williams Syndrome.

WILLIAMS SYNDROME: REPORT OF A CASE REFLECTING PULMONARY VALVE STENOSIS A patient affected by Williams Syndrome is described. He presented “elfin face”, neurological disorders and cardiac malformations. The presence of a severe pulmonary valve stenosis is pointed out. This type of malformation is rare in Williams Syndrome.